GCH1 mutations in dopa-responsive dystonia and Parkinson's disease.

Guanosine triphosphate cyclohydrolase I (GCH1) mutations are associated with increased risk for dopa-responsive dystonia (DRD) and Parkinson's disease (PD). Herein, we investigated the frequency of GCH1 mutations and clinical symptoms in patients with clinically diagnosed PD and DRD. We used the Sanger method to screen entire exons in 268 patients with PD and 26 patients with DRD, with the examinations of brain magnetic resonance imaging scans, striatal dopamine transporter scans, and [123I] metaiodobenzylguanidine (MIBG) myocardiac scintigraphy scans. We identified 15 patients with heterozygous GCH1 mutations from seven probands and five sporadic cases. The prevalence of GCH1 mutations in probands was different between PD [1.9% (5/268)] and DRD [26.9% (7/26)] (p value < 0.0001). The onset age tends to be different between PD and DRD patients: 35.4 ± 25.3 and 16.5 ± 13.6, respectively (average ± SD; p = 0.08). Most of the patients were women (14/15). Dystonia was common symptom, and dysautonomia and cognitive decline were uncommon in our PD and DRD. All patients presented mild parkinsonism or dystonia with excellent response to levodopa. Seven of seven DRD and three of five PD presented normal heart-to-mediastinum ratio on MIBG myocardial scintigraphy. Five of six DRD and three of four PD demonstrated normal densities of dopamine transporter. Our findings elucidated the clinical characteristics of PD and DRD patients due to GCH1 mutations. PD patients with GCH1 mutations also had different symptoms from those seen in typical PD. The patients with GCH1 mutations had heterogeneous clinical symptoms.

Body Lateropulsion and Cerebellar Tremor in a Patient with Pontine Infarction.

Body lateropulsion is known to be caused commonly by lateral medullary lesions but rarely by pontine lesions. It is also known to be associated with lesions of the dorsal spinothalamic tract or ascending graviceptive pathways. We herein report the case of a 75-year-old woman presenting with contralateral lateropulsion and cerebellar tremor caused by pons infarction. To our knowledge, this is the first case report of pontine infarction causing both lateropulsion and cerebellar tremor. Our case may be helpful in anatomical studies of ascending graviceptive pathways.

The first case of POEMS syndrome with synchronous breast cancer: What are the associated diagnostic challenges?

Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, Skin changes (POEMS) syndrome is a rare plasma cell disorder that causes a paraneoplastic syndrome. We report the first case of POEMS syndrome with synchronous breast cancer. The patient was at risk of being misdiagnosed with metastatic cancer, and it is important to emphasize that physical examinations provided vital diagnostic clues.

Cerebral Venous Air Embolism due to a Hidden Skull Fracture Secondary to Head Trauma.

Cerebral venous air embolism is sometimes caused by head trauma. One of the paths of air entry is considered a skull fracture. We report a case of cerebral venous air embolism following head trauma. The patient was a 55-year-old man who fell and hit his head. A head computed tomography (CT) scan showed the air in the superior sagittal sinus; however, no skull fractures were detected. Follow-up CT revealed a fracture line in the right temporal bone. Cerebral venous air embolism following head trauma might have occult skull fractures even if CT could not show the skull fractures.

Amyloid ß-protein oligomers upregulate the ß-secretase, BACE1, through a post-translational mechanism involving its altered subcellular distribution in neurons.

BACKGROUND: ß-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is a membrane-bound aspartyl protease that initiates amyloid ß-protein (Aß) generation. Aberrant elevation of BACE1 levels in brains of Alzheimer's disease (AD) patients may involve Aß. In the present study, we used a neuron culture model system to investigate the effects of Aß on BACE1 expression as well as the underlying mechanisms. RESULTS: Rat primary cortical neurons were treated with relatively low concentrations (2.5 µM) of Aß42 oligomers (Aß-O) or fibrils (Aß-F) for 2-3 days. Aß-O induced a significant increase in protein levels of BACE1, while Aß-F only had a marginal effect. Levels of amyloid precursor protein (APP) and the major α-secretase, ADAM10, remained unaltered upon treatment with both types of Aß. Aß-O treatment resulted in activation of eIF2α and caspase 3 in a time-dependent manner, with no changes in the endoplasmic reticulum (ER) stress marker, GRP78, indicating that a typical ER stress response is not induced under our experimental conditions. Furthermore, Aß-O did not affect BACE1 mRNA expression but augmented the levels of exogenous BACE1 expressed via recombinant adenoviruses, indicating regulation of BACE1 protein expression, not at the transcriptional or translational but the post-translational level. Immunocytochemical analysis revealed that Aß-O causes a significant increase in BACE1 immunoreactivity in neurites (both axons and dendrites), but not soma of neurons; this change appears relevant to the mechanism of Aß-O-induced BACE1 elevation, which may involve impairment of BACE1 trafficking and degradation. In contrast, Aß-O had no effect on APP immunoreactivity. CONCLUSION: Our results collectively suggest that Aß oligomers induce BACE1 elevation via a post-translational mechanism involving its altered subcellular distribution in neurons, which possibly triggers a vicious cycle of Aß generation, thus contributing to the pathogenetic mechanism of AD.

LRP1 Downregulates the Alzheimer's ß-Secretase BACE1 by Modulating Its Intraneuronal Trafficking

The ß-secretase called BACE1 is a membrane-associated protease that initiates the generation of amyloid ß-protein (Aß), a key event in Alzheimer's disease (AD). However, the mechanism of intraneuronal regulation of BACE1 is poorly understood. Here, we present evidence that low-density lipoprotein receptor-related protein 1 (LRP1), a multi-functional receptor, has a previously unrecognized function to regulate BACE1 in neurons. We show that deficiency of LRP1 exerts promotive effects on the protein expression and function of BACE1, whereas expression of LRP-L4, a functional LRP1 mini-receptor, specifically decreases BACE1 levels in both human embryonic kidney (HEK) 293 cells and rat primary neurons, leading to reduced Aß production. Our subsequent analyses further demonstrate that (1) both endogenous and exogenous BACE1 and LRP1 interact with each other and are colocalized in soma and neurites of primary neurons, (2) LRP1 reduces the protein stability and cell-surface expression of BACE1, and (3) LRP1 facilitates the shift in intracellular localization of BACE1 from early to late endosomes, thereby promoting lysosomal degradation. These findings establish that LRP1 specifically downregulates BACE1 by modulating its intraneuronal trafficking and stability through protein interaction and highlight LRP1 as a potential therapeutic target in AD.

Statins reduce amyloid ß-peptide production by modulating amyloid precursor protein maturation and phosphorylation through a cholesterol-independent mechanism in cultured neurons.

Statins, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, have been reported to attenuate amyloid-ß peptide (Aß) production in various cellular models. However, the mechanisms by which statins affect neuronal Aß production have not yet been clarified. Here, we investigated this issue in rat primary cortical neurons using two statins, pitavastatin (PV) and atorvastatin (AV). Treatment of neurons with 0.2-2.5 µM PV or AV for 4 days induced a concentration- and time-dependent reduction in the secretion of both Aß40 and Aß42. Moreover, Western blot analyses of cell lysates showed that treatment with PV or AV significantly reduced expression levels of the mature form of amyloid precursor protein (APP) and Thr668-phosphorylated APP (P-APP), but not immature form of APP; the decreases in P-APP levels were more notable than those of mature APP levels. The statin treatment did not alter expression of BACE1 (ß-site APP-cleaving enzyme 1) or γ-secretase complex proteins (presenilin 1, nicastrin, APH-1, and PEN-2). In neurons overexpressing APP via recombinant adenoviruses, PV or AV similarly reduced Aß secretion and the levels of mature APP and P-APP. Statins also markedly reduced cellular cholesterol content in neurons in a concentration-dependent manner. Co-treatment with mevalonate reversed the statin-induced decreases in Aß secretion and mature APP and P-APP levels, whereas co-treatment with cholesterol did not, despite recovery of cellular cholesterol levels. Finally, cell-surface biotinylation experiments revealed that both statins significantly reduced the levels of cell-surface P-APP without changing those of cell surface mature APP. These results suggest that statins reduce Aß production by selectively modulating APP maturation and phosphorylation through a mechanism independent of cholesterol reduction in cultured neurons.

An ocular form of myasthenia gravis with a high titer of anti-MuSK antibodies during a long-term follow-up.

We herein report a case of ocular myasthenia gravis (MG) that was highly positive for anti-muscle-specific tyrosine kinase (MuSK) antibodies. The examined patient exhibited bilateral ptosis and lateral gaze palsy without any generalized symptoms and was diagnosed with ocular MG with anti-MuSK antibodies. She responded to treatment with prednisolone and immunosuppressants and experienced only ocular symptoms for four years and eight months after onset. Ocular MG with anti-MuSK antibodies lasting for a long term has rarely been described. Our findings suggest that it may be reasonable to test for the presence of anti-MuSK antibodies in patients who present with external ophthalmoplegia.

Neuronal ß-amyloid generation is independent of lipid raft association of ß-secretase BACE1: analysis with a palmitoylation-deficient mutant.

ß-Secretase, BACE1 is a neuron-specific membrane-associated protease that cleaves amyloid precursor protein (APP) to generate ß-amyloid protein (Aß). BACE1 is partially localized in lipid rafts. We investigated whether lipid raft localization of BACE1 affects Aß production in neurons using a palmitoylation-deficient mutant and further analyzed the relationship between palmitoylation of BACE1 and its shedding and dimerization. We initially confirmed that BACE1 is mainly palmitoylated at four C-terminal cysteine residues in stably transfected neuroblastoma cells. We found that raft localization of mutant BACE1 lacking the palmitoylation modification was markedly reduced in comparison to wild-type BACE1 in neuroblastoma cells as well as rat primary cortical neurons expressing BACE1 via recombinant adenoviruses. In primary neurons, expression of wild-type and mutant BACE1 enhanced production of Aß from endogenous or overexpressed APP to similar extents with the ß-C-terminal fragment (ß-CTF) of APP mainly distributed in nonraft fractions. Similarly, ß-CTF was recovered mainly in nonraft fractions of neurons expressing Swedish mutant APP only. These results show that raft association of BACE1 does not influence ß-cleavage of APP and Aß production in neurons, and support the view that BACE1 cleaves APP mainly in nonraft domains. Thus, we propose a model of neuronal Aß generation involving mobilization of ß-CTF from nonraft to raft domains. Additionally, we obtained data indicating that palmitoylation plays a role in BACE1 shedding but not dimerization.

A Japanese case of fragile-X-associated tremor/ataxia syndrome (FXTAS).

A 71-year-old man developed postural tremor and was treated as an essential tremor patient. Nine years after the tremor onset, he developed symptoms resembling Fragile-X-associated tremor/ataxia syndrome (FXTAS), including exacerbated (increased coarseness and amplitude) tremor in the right arm, ataxic gait, and brain MRI showed lesions in the bilateral middle cerebellar peduncles (MCP). Evidence of premutation in the form of 83 CGG repeats of the Fragile-X-mental retardation 1 (FMR1) gene confirmed the diagnosis of FXTAS. FXTAS causes various neurological symptoms including in some cases tremor resembling essential tremor in the early stages. FMR1 gene premutation should be checked when the patient develops intention tremor, cerebral dysfunction and/or a brain MRI shows MCP lesions.

A case of idiopathic hypertrophic cranial pachymeningitis presenting high values of matrix metalloproteinase.

This report concerns a 53-year-old male patient with idiopathic hypertrophic cranial pachymeningitis who presented with multiple cranial nerve palsies (I, II, III, IV, V, VI). Brain magnetic resonance imaging showed diffuse thickening and gadolinium enhancement of the cerebral dura mater. A biopsy of the cerebral dura mater showed granulomatous vasculitis with histiocyte infiltration. Although both the serum rheumatoid factor (RF) and matrix metalloproteinase-3 (MMP-3) were high, the patient showed no signs of arthritis. He was anti-cyclic citrullinated peptide antibody negative, which makes the presence of comorbid chronic rheumatoid arthritis (RA) unlikely. The aetiology of the pachymeningitis was unknown, which led to the diagnosis of idiopathic hypertrophic cranial pachymeningitis. Steroid pulse therapy successfully diminished the patient's pachymeningitis and lowered both RF and MMP-3. High values of RF suggest the possible involvement of an autoimmune mechanism, and the MMP value may be an important indicator of the aetiology of pachymeningitis with granulomatous vasculitis.

Intravascular large B cell lymphoma with neurological symptoms diagnosed on the basis of a senile angioma-like eruption.

Intravascular large B cell lymphoma (IVLBCL) presents various neurological symptoms, and the prognosis frequently deteriorates with a delay in diagnosis. In addition, for the diagnosis of IVLBCL, invasive biopsies are generally performed in main organs, such as the brain. We report a case of IVLBCL in which an early diagnosis was enabled by skin biopsy. The patient in this case had cauda equine syndrome and had developed multiple brain infarctions. She received six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) treatment and is currently in complete remission. At the macroscopic level, her lesions resembled senile angioma, commonly observed in normal elderly persons. Eruptions of this type are not currently recognised as IVLBCL lesions and might easily be overlooked. In cases in which IVLBCL could be suspected, an active search and biopsy of skin lesions, including an eruption of this type, are useful for early diagnosis and treatment.

[Intravascular lymphomatosis manifesting clinically as subacute encephalopathy].

We report a 62-year-old woman with intravascular lymphomatosis (IVL) which presented as subacute encephalopathy. She was admitted to our hospital because of loss of consciousness in the middle of February, 2006. Laboratory tests indicated elevated serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and cerebrospinal fluid protein. Magnetic resonance imaging (MRI) of the brain revealed multiple infarct-like lesions mainly in the white matter. After admission, her consciousness was soon improved, but the inflammatory response did not disappear with any antibiotics or virucides. Her consciousness was not exacerbated, and she was discharged in the middle of March, although the reason for loss of consciousness remained unknown. After discharge she developed an abnormal behavior and mental deterioration, and therefore she was readmitted late in March. On second admission, her consciousness was drowsy. Neurological examinations revealed conjugate deviation of her eyes to the left, left hemiparesis, and generalized hyporeflexia. Laboratory tests showed more elevated CRP than that of the last time, and raised soluble IL-2 receptor (sIL-2R). The repeated MRI of the brain disclosed that initial lesions of the white matter progressively enlarged and increased in number. To make an appropriate diagnosis of the lesions on the brain MRI, the open brain biopsy was performed. Microscopic examination showed that many small vessels were occluded by lymphoma cells (B-lymphocytes) with hemorrhage, and IVL was diagnosed. She was treated with regimens of combined chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone). After chemotherapy her consciousness and left hemiparesis were gradually improved and the levels of CRP were normalized. The infarcts-like lesions detected on the brain MRI became reduced and decreased. IVL is a rare disease, and the prognosis is generally poor, with a rapidly fatal outcome, leading to a postmortem diagnosis. In the present report, we successfully treated the patient by rituximab in addition to standard CHOP therapy. Rituximab may play an important role in the treatment of IVL.